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Use of mouse models in studying type 2 diabetes mellitus

Published online by Cambridge University Press:  06 January 2011

Angela W.S. Lee  and
Roger D. Cox
Angela W.S. Lee*
Affiliation:
Metabolism and Inflammation, MRC Mammalian Genetics Unit, Harwell Oxford, UK.
Roger D. Cox
Affiliation:
Metabolism and Inflammation, MRC Mammalian Genetics Unit, Harwell Oxford, UK.
*
*Corresponding author: Angela W.S. Lee, MRC Mammalian Genetics Unit, Harwell Oxford, Oxfordshire, OX11 0RD, UK. E-mail: a.lee@har.mrc.ac.uk
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Abstract

The use of mouse models in medical research has greatly contributed to our understanding of the development of type 2 diabetes mellitus and the mechanisms of disease progression in the context of insulin resistance and β-cell dysfunction. Maintenance of glucose homeostasis involves a complex interplay of many genes and their actions in response to exogenous stimuli. In recent years, the availability of large population-based cohorts and the capacity to genotype enormous numbers of common genetic variants have driven various large-scale genome-wide association studies, which has greatly accelerated the identification of novel genes likely to be involved in the development of type 2 diabetes. The increasing demand for verifying novel genes is met by the timely development of new mouse resources established as various collaborative projects involving major transgenic and phenotyping centres and laboratories worldwide. The surge of new data will ultimately enable translational research into potential improvement and refinement of current type 2 diabetes therapy options, and hopefully restore quality of life for patients.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 12 , January 2010 , e40
Copyright
Copyright © Cambridge University Press 2010

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References

References

1Roglic, G. et al. (2005) The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 28, 2130–2135CrossRefGoogle ScholarPubMed
2Donnelly, R. et al. (2000) ABC of arterial and venous disease: vascular complications of diabetes. British Medical Journal 320, 1062–1066CrossRefGoogle ScholarPubMed
3Morrish, N.J. et al. (2001) Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44 (Supplement 2), S14–S21CrossRefGoogle ScholarPubMed
4Song, S.H. and Hardisty, C.A. (2008) Early-onset type 2 diabetes mellitus: an increasing phenomenon of elevated cardiovascular risk. Expert Review of Cardiovascular Therapy 6, 315–322CrossRefGoogle ScholarPubMed
5Hatunic, M. et al. (2005) Contrasting clinical and cardiovascular risk status between early and later onset type 2 diabetes. Diabetes and Vascular Disease Research 2, 73–75CrossRefGoogle ScholarPubMed
6Steinberger, J. et al. (2001) Adiposity in childhood predicts obesity and insulin resistance in young adulthood. Jornal de Pediatria 138, 469–473CrossRefGoogle ScholarPubMed
7Permutt, M.A., Wasson, J. and Cox, N. (2005) Genetic epidemiology of diabetes. Journal of Clinical Investigation 115, 1431–1439CrossRefGoogle ScholarPubMed
8Stumvoll, M., Goldstein, B.J. and van Haeften, T.W. (2005) Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346CrossRefGoogle ScholarPubMed
9Mills, G.W. et al. (2004) Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to type 2 diabetes. Diabetologia 47, 732–738CrossRefGoogle ScholarPubMed
10Vimaleswaran, K.S. and Loos, R.J. (2010) Progress in the genetics of common obesity and type 2 diabetes. Expert Reviews in Molecular Medicine 12, e7CrossRefGoogle ScholarPubMed
11Dupuis, J. et al. (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics 42, 105–116CrossRefGoogle ScholarPubMed
12Saxena, R. et al. (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nature Genetics 42, 142–148CrossRefGoogle Scholar
13Voight, B.F. et al. (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature Genetics 42, 579–589CrossRefGoogle ScholarPubMed
14Soranzo, N. et al. (2010) Common variants at ten genomic loci influence hemoglobin A1C levels via glycemic and non-glycemic pathways. Diabetes Sep 21; [Epub ahead of print]CrossRefGoogle Scholar
15Peters, L.L. et al. (2007) The mouse as a model for human biology: a resource guide for complex trait analysis. Nature Reviews. Genetics 8, 58–69CrossRefGoogle Scholar
16Rosenthal, N. and Brown, S. (2007) The mouse ascending: perspectives for human-disease models. Nature Cell Biology 9, 993–999CrossRefGoogle ScholarPubMed
17Fuchs, H. et al. (2009) The German Mouse Clinic: a platform for systemic phenotype analysis of mouse models. Current Pharmaceutical Biotechnology 10, 236–243CrossRefGoogle Scholar
18Mallon, A.M., Blake, A. and Hancock, J.M. (2008) EuroPhenome and EMPReSS: online mouse phenotyping resource. Nucleic Acids Research 36, D715–D718CrossRefGoogle ScholarPubMed
19Coleman, D.L. (1973) Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9, 294–298CrossRefGoogle ScholarPubMed
20Halaas, J.L. et al. (1995) Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546CrossRefGoogle ScholarPubMed
21Chen, H. et al. (1996) Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495CrossRefGoogle ScholarPubMed
22Lee, G.H. et al. (1996) Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635CrossRefGoogle ScholarPubMed
23Asensio, C. et al. (2004) Changes in glycemia by leptin administration or high-fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis. Endocrinology 145, 2206–2213CrossRefGoogle ScholarPubMed
24Srinivasan, K. and Ramarao, P. (2007) Animal models in type 2 diabetes research: an overview. Indian J Med Res 125, 451–472Google ScholarPubMed
25Chatzigeorgiou, A. et al. (2009) The use of animal models in the study of diabetes mellitus. In Vivo 23, 245–258Google Scholar
26Yoshioka, M. et al. (1997) A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 46, 887–894CrossRefGoogle ScholarPubMed
27Mathews, C.E., Langley, S.H. and Leiter, E.H. (2002) New mouse model to study islet transplantation in insulin-dependent diabetes mellitus. Transplantation 73, 1333–1336CrossRefGoogle ScholarPubMed
28Lakso, M. et al. (1992) Targeted oncogene activation by site-specific recombination in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 89, 6232–6236CrossRefGoogle ScholarPubMed
29Orban, P.C., Chui, D. and Marth, J.D. (1992) Tissue- and site-specific DNA recombination in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 89, 6861–6865CrossRefGoogle ScholarPubMed
30Akagi, K. et al. (1997) Cre-mediated somatic site-specific recombination in mice. Nucleic Acids Research 25, 1766–1773CrossRefGoogle ScholarPubMed
31Feil, R. et al. (1997) Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochemical and Biophysical Research Communications 237, 752–757CrossRefGoogle ScholarPubMed
32Kim, J.E., Nakashima, K. and de Crombrugghe, B. (2004) Transgenic mice expressing a ligand-inducible cre recombinase in osteoblasts and odontoblasts: a new tool to examine physiology and disease of postnatal bone and tooth. American Journal of Pathology 165, 1875–1882CrossRefGoogle ScholarPubMed
33Hayashi, S. and McMahon, A.P. (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. Developmental Biology 244, 305–318CrossRefGoogle ScholarPubMed
34Remedi, M.S. et al. (2009) Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus. Cell Metabolism 9, 140–151CrossRefGoogle Scholar
35Koch, L. et al. (2008) Central insulin action regulates peripheral glucose and fat metabolism in mice. Journal of Clinical Investigation 118, 2132–2147Google ScholarPubMed
36Ernst, M.B. et al. (2009) Enhanced Stat3 activation in POMC neurons provokes negative feedback inhibition of leptin and insulin signaling in obesity. Journal of Neuroscience 29, 11582–11593CrossRefGoogle ScholarPubMed
37Girard, C.A. et al. (2009) Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes. Journal of Clinical Investigation 119, 80–90Google ScholarPubMed
38Soriano, P. (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nature Genetics 21, 70–71CrossRefGoogle ScholarPubMed
39Belgardt, B.F. et al. (2008) PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metabolism 7, 291–301CrossRefGoogle ScholarPubMed
40Justice, M.J. et al. (1999) Mouse ENU mutagenesis. Human Molecular Genetics 8, 1955–1963CrossRefGoogle ScholarPubMed
41Hitotsumachi, S., Carpenter, D.A. and Russell, W.L. (1985) Dose-repetition increases the mutagenic effectiveness of N-ethyl-N-nitrosourea in mouse spermatogonia. Proceedings of the National Academy of Sciences of the United States of America 82, 6619–6621CrossRefGoogle ScholarPubMed
42Frayling, T.M. et al. (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894CrossRefGoogle ScholarPubMed
43Church, C. et al. (2009) A mouse model for the metabolic effects of the human fat mass and obesity associated FTO gene. PLoS Genetics 5, e1000599CrossRefGoogle ScholarPubMed
44Fischer, J. et al. (2009) Inactivation of the Fto gene protects from obesity. Nature 458, 894–898CrossRefGoogle ScholarPubMed
45Nolan, P.M. et al. (2000) A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse. Nature Genetics 25, 440–443CrossRefGoogle ScholarPubMed
46Hrabe de Angelis, M.H. et al. (2000) Genome-wide, large-scale production of mutant mice by ENU mutagenesis. Nature Genetics 25, 444–447CrossRefGoogle ScholarPubMed
47Aigner, B. et al. (2008) Diabetes models by screen for hyperglycaemia in phenotype-driven ENU mouse mutagenesis projects. American Journal of Physiology. Endocrinology and Metabolism 294, E232–240CrossRefGoogle ScholarPubMed
48Toye, A.A. et al. (2004) A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. Diabetes 53, 1577–1583CrossRefGoogle ScholarPubMed
49Grupe, A. et al. (1995) Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Cell 83, 69–78CrossRefGoogle ScholarPubMed
50Bali, D. et al. (1995) Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene. Journal of Biological Chemistry 270, 21464–21467CrossRefGoogle ScholarPubMed
51Goldsworthy, M. et al. (2008) Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance. Diabetes 57, 2234–2244CrossRefGoogle ScholarPubMed
52Nandi, A. et al. (2004) Mouse models of insulin resistance. Physiological Reviews 84, 623–647CrossRefGoogle ScholarPubMed
53Pirola, L., Johnston, A.M. and Van Obberghen, E. (2004) Modulation of insulin action. Diabetologia 47, 170–184CrossRefGoogle ScholarPubMed
54Nakae, J., Kido, Y. and Accili, D. (2001) Distinct and overlapping functions of insulin and IGF-I receptors. Endocrine Reviews 22, 818–835CrossRefGoogle ScholarPubMed
55Shepherd, P.R., Withers, D.J. and Siddle, K. (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochemical Journal 333 (Pt 3), 471–490CrossRefGoogle ScholarPubMed
56Thorens, B. (1996) Glucose transporters in the regulation of intestinal, renal, and liver glucose fluxes. American Journal of Physiology 270, G541–553Google ScholarPubMed
57Accili, D. et al. (1996) Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nature Genetics 12, 106–109CrossRefGoogle Scholar
58Joshi, R.L. et al. (1996) Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO Journal 15, 1542–1547CrossRefGoogle ScholarPubMed
59Kim, J.K. et al. (2000) Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. Journal of Clinical Investigation 105, 1791–1797CrossRefGoogle ScholarPubMed
60Bruning, J.C. et al. (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Molecular Cell 2, 559–569CrossRefGoogle ScholarPubMed
61Bluher, M. et al. (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Developmental Cell 3, 25–38CrossRefGoogle ScholarPubMed
62Bluher, M. et al. (2004) Intrinsic heterogeneity in adipose tissue of fat-specific insulin receptor knock-out mice is associated with differences in patterns of gene expression. Journal of Biological Chemistry 279, 31891–31901CrossRefGoogle ScholarPubMed
63Bluher, M., Kahn, B.B. and Kahn, C.R. (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574CrossRefGoogle ScholarPubMed
64Lauro, D. et al. (1998) Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue. Nature Genetics 20, 294–298CrossRefGoogle ScholarPubMed
65Michael, M.D. et al. (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Molecular Cell 6, 87–97CrossRefGoogle ScholarPubMed
66Bruning, J.C. et al. (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125CrossRefGoogle ScholarPubMed
67Fernandez, A.M. et al. (2001) Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes and Development 15, 1926–1934CrossRefGoogle ScholarPubMed
68Bruning, J.C. et al. (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572CrossRefGoogle ScholarPubMed
69Araki, E. et al. (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190CrossRefGoogle ScholarPubMed
70Tamemoto, H. et al. (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186CrossRefGoogle ScholarPubMed
71Withers, D.J. et al. (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904CrossRefGoogle ScholarPubMed
72Carvalho, E. et al. (2005) Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle. American Journal of Physiology. Endocrinology and Metabolism 289, E551–561CrossRefGoogle ScholarPubMed
73Zisman, A. et al. (2000) Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nature Medicine 6, 924–928CrossRefGoogle ScholarPubMed
74Kim, Y.B. et al. (2005) Muscle-specific deletion of the Glut4 glucose transporter alters multiple regulatory steps in glycogen metabolism. Molecular and Cellular Biology 25, 9713–9723CrossRefGoogle ScholarPubMed
75Abel, E.D. et al. (2001) Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 409, 729–733CrossRefGoogle ScholarPubMed
76Kotani, K. et al. (2004) GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. Journal of Clinical Investigation 114, 1666–1675CrossRefGoogle ScholarPubMed
77Katz, E.B. et al. (1995) Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377, 151–155CrossRefGoogle Scholar
78Stenbit, A.E. et al. (1997) GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nature Medicine 3, 1096–1101CrossRefGoogle ScholarPubMed
79Ren, J.M. et al. (1995) Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice. Journal of Clinical Investigation 95, 429–432CrossRefGoogle ScholarPubMed
80Gibbs, E.M. et al. (1995) Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4). Journal of Clinical Investigation 95, 1512–1518CrossRefGoogle ScholarPubMed
81Cho, H. et al. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292, 1728–1731CrossRefGoogle Scholar
82Terauchi, Y. et al. (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nature Genetics 21, 230–235CrossRefGoogle ScholarPubMed
83Aoki, K. et al. (2009) Role of the liver in glucose homeostasis in PI 3-kinase p85alpha-deficient mice. American Journal of Physiology. Endocrinology and Metabolism 296, E842–853CrossRefGoogle ScholarPubMed
84Mauvais-Jarvis, F. et al. (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. Journal of Clinical Investigation 109, 141–149CrossRefGoogle ScholarPubMed
85Elchebly, M. et al. (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548CrossRefGoogle ScholarPubMed
86Klaman, L.D. et al. (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Molecular and Cellular Biology 20, 5479–5489CrossRefGoogle ScholarPubMed
87Nakae, J. et al. (2002) Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nature Genetics 32, 245–253CrossRefGoogle ScholarPubMed
88He, W. et al. (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences of the United States of America 100, 15712–15717CrossRefGoogle Scholar
89Zhang, J. et al. (2004) Selective disruption of PPARgamma 2 impairs the development of adipose tissue and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 101, 10703–10708CrossRefGoogle ScholarPubMed
90Yang, C. et al. (2001) Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance. Journal of Clinical Investigation 107, 1311–1318CrossRefGoogle ScholarPubMed
91Wojtaszewski, J.F. et al. (1999) Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. Journal of Clinical Investigation 104, 1257–1264CrossRefGoogle ScholarPubMed
92Samuel, V., Petersen, K. and Shulman, G.I. (2010) Lipid-induced insulin resistance: unravelling the mechanism. The Lancet 375, 2267–2277CrossRefGoogle ScholarPubMed
93Jones, J.R. et al. (2005) Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America 102, 6207–6212CrossRefGoogle ScholarPubMed
94Okamoto, H. et al. (2004) Transgenic rescue of insulin receptor-deficient mice. Journal of Clinical Investigation 114, 214–223CrossRefGoogle ScholarPubMed
95Kubota, N. et al. (2000) Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49, 1880–1889CrossRefGoogle ScholarPubMed
96Ravichandran, L.V. et al. (2001) Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor. Molecular Endocrinology 15, 1768–1780CrossRefGoogle ScholarPubMed
97Nakae, J. et al. (2003) The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Developmental Cell 4, 119–129CrossRefGoogle ScholarPubMed
98Chang-Chen, K.J., Mullur, R. and Bernal-Mizrachi, E. (2008) Beta-cell failure as a complication of diabetes. Reviews in Endocrine and Metabolic Disorder 9, 329–343CrossRefGoogle ScholarPubMed
99Guillam, M.T. et al. (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nature Genetics 17, 327–330CrossRefGoogle ScholarPubMed
100Postic, C. et al. (1999) Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. Journal of Biological Chemistry 274, 305–315CrossRefGoogle ScholarPubMed
101Remedi, M.S. et al. (2005) ATP-sensitive K+ channel signaling in glucokinase-deficient diabetes. Diabetes 54, 2925–2931CrossRefGoogle ScholarPubMed
102Terauchi, Y. et al. (1997) Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. Genetic reconstitution of diabetes as a polygenic disease. Journal of Clinical Investigation 99, 861–866CrossRefGoogle ScholarPubMed
103Freeman, H.C. et al. (2006) Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 55, 2153–2156CrossRefGoogle ScholarPubMed
104Huang, T.T. et al. (2006) Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Human Molecular Genetics 15, 1187–1194CrossRefGoogle ScholarPubMed
105Toye, A.A. et al. (2005) A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia 48, 675–686CrossRefGoogle ScholarPubMed
106Miki, T. et al. (1998) Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 95, 10402–10406CrossRefGoogle ScholarPubMed
107Remedi, M.S. et al. (2006) Hyperinsulinism in mice with heterozygous loss of K(ATP) channels. Diabetologia 49, 2368–2378CrossRefGoogle ScholarPubMed
108Koster, J.C. et al. (2002) Hyperinsulinism induced by targeted suppression of beta cell KATP channels. Proceedings of the National Academy of Sciences of the United States of America 99, 16992–16997CrossRefGoogle ScholarPubMed
109Koster, J.C. et al. (2000) Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 100, 645–654CrossRefGoogle ScholarPubMed
110Koster, J.C. et al. (2006) Expression of ATP-insensitive KATP channels in pancreatic beta-cells underlies a spectrum of diabetic phenotypes. Diabetes 55, 2957–2964CrossRefGoogle ScholarPubMed
111Shiota, C. et al. (2002) Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. Journal of Biological Chemistry 277, 37176–37183CrossRefGoogle ScholarPubMed
112Seghers, V. et al. (2000) Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. Journal of Biological Chemistry 275, 9270–9277CrossRefGoogle Scholar
113Kulkarni, R.N. et al. (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96, 329–339CrossRefGoogle ScholarPubMed
114Pound, L.D. et al. (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochemical Journal 421, 371–376CrossRefGoogle ScholarPubMed
115Ahlgren, U. et al. (1998) Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes and Development 12, 1763–1768CrossRefGoogle ScholarPubMed
116Gupta, R.K. et al. (2005) The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. Journal of Clinical Investigation 115, 1006–1015CrossRefGoogle ScholarPubMed
117Miura, A. et al. (2006) Hepatocyte nuclear factor-4alpha is essential for glucose-stimulated insulin secretion by pancreatic beta-cells. Journal of Biological Chemistry 281, 5246–5257CrossRefGoogle ScholarPubMed
118Lee, Y.H., Sauer, B. and Gonzalez, F.J. (1998) Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse. Molecular and Cellular Biology 18, 3059–3068CrossRefGoogle ScholarPubMed
119Pontoglio, M. et al. (1998) Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. Journal of Clinical Investigation 101, 2215–2222CrossRefGoogle ScholarPubMed
120Wang, L. et al. (2004) Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release. Endocrinology 145, 3941–3949CrossRefGoogle ScholarPubMed
121Naya, F.J. et al. (1997) Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes and Development 11, 2323–2334CrossRefGoogle ScholarPubMed
122Vaxillaire, M. and Froguel, P. (2009) Monogenic forms of diabetes mellitus: an update. Endocrinol Nutr 56 (Supplement 4), 26–29CrossRefGoogle ScholarPubMed
123Vaxillaire, M. and Froguel, P. (2008) Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocrine Reviews 29, 254–264CrossRefGoogle Scholar
124Aguilar-Bryan, L. et al. (1998) Toward understanding the assembly and structure of KATP channels. Physiological Reviews 78, 227–245CrossRefGoogle ScholarPubMed
125Flanagan, S.E. et al. (2009) Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human Mutation 30, 170–180CrossRefGoogle ScholarPubMed
126Shimomura, K. et al. (2009) Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO Molecular Medicine 1, 166–177CrossRefGoogle ScholarPubMed
127Gloyn, A.L. et al. (2004) Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New England Journal of Medicine 350, 1838–1849CrossRefGoogle ScholarPubMed
128Nestorowicz, A. et al. (1997) A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 46, 1743–1748CrossRefGoogle ScholarPubMed
129Huopio, H. et al. (2002) K(ATP) channels and insulin secretion disorders. American Journal of Physiology. Endocrinology and Metabolism 283, E207–216CrossRefGoogle ScholarPubMed
130Hugill, A. et al. (2010) A mutation in KCNJ11 causing human hyperinsulinism (Y12X) results in a glucose-intolerant phenotype in the mouse. Diabetologia 53, 2352–2356CrossRefGoogle Scholar
131Zeggini, E. et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341CrossRefGoogle ScholarPubMed
132Sladek, R. et al. (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885CrossRefGoogle ScholarPubMed
133Grant, S.F. et al. (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genetics 38, 320–323CrossRefGoogle ScholarPubMed
134Shao, S. et al. (2009) Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells. Biochemical and Biophysical Research Communications 384, 401–404CrossRefGoogle ScholarPubMed
135Fajans, S.S., Bell, G.I. and Polonsky, K.S. (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New England Journal of Medicine 345, 971–980CrossRefGoogle ScholarPubMed
136Schmidt, C. et al. (2008) A meta-analysis of QTL for diabetes-related traits in rodents. Physiological Genomics 34, 42–53CrossRefGoogle ScholarPubMed
137Kim, J.H. et al. (2001) Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics 74, 273–286CrossRefGoogle ScholarPubMed
138Kim, J.H. et al. (2005) Type 2 diabetes mouse model TallyHo carries an obesity gene on chromosome 6 that exaggerates dietary obesity. Physiological Genomics 22, 171–181CrossRefGoogle ScholarPubMed
139Frazer, K.A. et al. (2007) A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448, 1050–1053CrossRefGoogle ScholarPubMed
140Valdar, W. et al. (2006) Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genetics 38, 879–887CrossRefGoogle ScholarPubMed
141Churchill, G.A. et al. (2004) The collaborative cross, a community resource for the genetic analysis of complex traits. Nature Genetics 36, 1133–1137Google Scholar
142Mott, R. et al. (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. Proceedings of the National Academy of Sciences of the United States of America 97, 12649–12654CrossRefGoogle ScholarPubMed
143Ghazalpour, A. et al. (2008) High-resolution mapping of gene expression using association in an outbred mouse stock. PLoS Genetics 4, e1000149CrossRefGoogle Scholar
144Newgard, C.B. and Attie, A.D. (2010) Getting biological about the genetics of diabetes. Nature Medicine 16, 388–391CrossRefGoogle ScholarPubMed
145Ingelsson, E. et al. (2010) Detailed physiologic characterization reveals diverse mechanisms for novel genetic loci regulating glucose and insulin metabolism in humans. Diabetes 59, 1266–1275CrossRefGoogle ScholarPubMed
146Grubb, S.C. et al. (2009) Mouse phenome database. Nucleic Acids Research 37, D720–730CrossRefGoogle ScholarPubMed
147Colagiuri, S. (2010) Diabesity: therapeutic options. Diabetes Obesity and Metabolism 12, 463–473CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Beckers, J., Wurst, W. and de Angelis, M.H. (2009) Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling. Nature Reviews Genetics 10, 371–380CrossRefGoogle ScholarPubMed
Tahrani, A.A. et al. (2010) Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacology and Therapeutics 125, 328–361CrossRefGoogle ScholarPubMed
Newgard, C.B. and Attie, A.D. (2010) Getting biological about the genetics of diabetes. Nature Medicine 16, 388–391CrossRefGoogle ScholarPubMed
Qatanani, M. and Lazar, M.A. (2007) Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes and Development 21, 1443–1455CrossRefGoogle ScholarPubMed
Smushkin, G. and Vella, A. (2010) Genetics of type 2 diabetes. Current Opinion in Clinical Nutrition and Metabolic Care 13, 471–477CrossRefGoogle ScholarPubMed
Zhang, B.B., Zhou, G. and Li, C. (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metabolism 9, 407–416CrossRefGoogle ScholarPubMed
Online Mendelian Inheritance in Man (database of human genes and genetic phenotypes):http://www.ncbi.nlm.nih.gov/omim/Google Scholar
Knockout mice production centres: http://www.eucomm.org (EUCOMM) http://www.nih.gov/science/models/mouse/knockout (KOMP) http://www.norcomm.org (NorCOMM)Google Scholar
Providers of mouse lines, frozen embryos and sperm: http://www.emmanet.org (EMMA) http://jaxmice.jax.org/list/int_ra7.html (JAX mice; mouse models for diabetes and obesity research)Google Scholar
Databases of phenotypes of knockouts and inbred strains: http://www.europhenome.org (EuroPhenome) http://phenome.jax.org (Mouse Phenome Database, MPD)Google Scholar
EMPReSS (database of standard operating procedures for mouse phenotyping): http://empress.har.mrc.ac.ukGoogle Scholar
Websites of ongoing and completed mouse mutagenesis and phenotyping projects: http://www.eumodic.org (EUMODIC consortium) http://www.eumorphia.org (EUMORPHIA consortium) http://www.knockoutmouse.org (IKMC)Google Scholar
The Coordination and Sustainability of International Mouse Informatics Resources (CASIMIR) project aims to coordinate and integrate several site databases in mouse functional genomics: http://www.casimir.org.ukGoogle Scholar
The Mouse Metabolic Phenotyping Centre (MMPC) consists of a group of laboratories in the USA that are dedicated to expert metabolic phenotyping for outside investigators: http://www.mmpc.orgGoogle Scholar
Beckers, J., Wurst, W. and de Angelis, M.H. (2009) Towards better mouse models: enhanced genotypes, systemic phenotyping and envirotype modelling. Nature Reviews Genetics 10, 371–380CrossRefGoogle ScholarPubMed
Tahrani, A.A. et al. (2010) Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacology and Therapeutics 125, 328–361CrossRefGoogle ScholarPubMed
Newgard, C.B. and Attie, A.D. (2010) Getting biological about the genetics of diabetes. Nature Medicine 16, 388–391CrossRefGoogle ScholarPubMed
Qatanani, M. and Lazar, M.A. (2007) Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes and Development 21, 1443–1455CrossRefGoogle ScholarPubMed
Smushkin, G. and Vella, A. (2010) Genetics of type 2 diabetes. Current Opinion in Clinical Nutrition and Metabolic Care 13, 471–477CrossRefGoogle ScholarPubMed
Zhang, B.B., Zhou, G. and Li, C. (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metabolism 9, 407–416CrossRefGoogle ScholarPubMed
Online Mendelian Inheritance in Man (database of human genes and genetic phenotypes):http://www.ncbi.nlm.nih.gov/omim/Google Scholar
Knockout mice production centres: http://www.eucomm.org (EUCOMM) http://www.nih.gov/science/models/mouse/knockout (KOMP) http://www.norcomm.org (NorCOMM)Google Scholar
Providers of mouse lines, frozen embryos and sperm: http://www.emmanet.org (EMMA) http://jaxmice.jax.org/list/int_ra7.html (JAX mice; mouse models for diabetes and obesity research)Google Scholar
Databases of phenotypes of knockouts and inbred strains: http://www.europhenome.org (EuroPhenome) http://phenome.jax.org (Mouse Phenome Database, MPD)Google Scholar
EMPReSS (database of standard operating procedures for mouse phenotyping): http://empress.har.mrc.ac.ukGoogle Scholar
Websites of ongoing and completed mouse mutagenesis and phenotyping projects: http://www.eumodic.org (EUMODIC consortium) http://www.eumorphia.org (EUMORPHIA consortium) http://www.knockoutmouse.org (IKMC)Google Scholar
The Coordination and Sustainability of International Mouse Informatics Resources (CASIMIR) project aims to coordinate and integrate several site databases in mouse functional genomics: http://www.casimir.org.ukGoogle Scholar
The Mouse Metabolic Phenotyping Centre (MMPC) consists of a group of laboratories in the USA that are dedicated to expert metabolic phenotyping for outside investigators: http://www.mmpc.orgGoogle Scholar